Embolization involves the partial or complete occlusion of blood vessels, limiting the flow of blood therethrough. The intentional occlusion of blood vessels (“therapeutic embolization”) may be used to treat a variety of vascular and non-vascular conditions including cerebral and peripheral aneurysms, ateriovenous malformation, uterine fibroids and to reduce blood flow to solid tumors including liver tumors. Embolization may be achieved by any number of means, including through the use of polymer microspheres.
In a typical embolization procedure, local anesthesia is first given over a common artery. The artery is then punctured and a catheter is inserted and fluoroscopically guided into the area of interest. An angiogram is performed by injecting contrast agent through the catheter, thereby visualizing the portion of the arterial tree downstream of the distal end of the catheter. Once the catheter is positioned in a site where deposition of an embolic composition or agent is desired, the composition or agent is deposited through the catheter. The embolic agent is generally selected based on the size of the vessel to be occluded, the desired duration of occlusion, and/or the type of disease or condition to be treated, among others factors. Following delivery of the embolic agent to the site within the vessel to be occluded, a follow-up angiogram can be performed to determine the specificity and completeness of the occlusion.
Embolic microspheres are typically composed of synthetic polymers, including without limitation polyvinyl alcohol (PVA), acetalized PVA (e.g., Contour SE™ embolic agent, Boston Scientific, Natick, Mass., USA) and crosslinked acrylic hydrogels (e.g., Embospheres®, Biosphere Medical, Rockland, Mass., USA). In some cases, embolic microspheres may include a therapeutic agent, such as a small molecule pharmaceutical agent (i.e. a drug), permitting concurrent vessel embolization and delivery of the drug to the vicinity of the embolized vessel. In one specific instance, a therapeutic agent (doxorubicin) has been directly added to polyvinyl alcohol hydrogel microspheres such that it can be released locally after delivery (the DC Bead™ drug delivery chemoembolization system, Biocompatibles International plc, Farnham, Surrey, UK). Other examples of commercially available microspheres include glass microspheres with entrapped radioisotopes such as 90Y (TheraSpheres™, MDS Nordion, Ottowa, Canada) and polymer microspheres that contain monomers that are capable of chelating radioisotopes including 90Y (SIR-Spheres®, SIRTex Medical, New South Wales, Australia).
While drug-loaded microspheres have a number of useful characteristics, they also have several limitations. For instance, commercially available drug eluting microspheres are generally biostable, and tend to remain in place even after they have delivered most of their drug preloads. And, they deliver those drug preloads relatively quickly: in vitro testing of currently available drug eluting microspheres loaded with chemotherapeutics shows that these microspheres release all or most of their drug payload in a single burst within about five hours; this rapid drug release may result in brief but high systemic dosing in cases where extended, local dosing is desired. In addition, drug eluting microspheres currently sold are not necessarily shelf-stable, and must be loaded with drug shortly before they are used. Finally, currently approved microsphere products are generally limited to delivering cationic drugs, meaning only a narrow subset of chemotherapeutics—doxorubicin and irinotecan—are compatible with currently-used microspheres.